1. Field of This Invention
This invention relates to a process for the production of p-(N-methyl)-amino benzoyl glutamic acid from p-(N-methyl)-amino-benzoic acid. This invention also relates to various intermediates in such process.
2. Prior Art
p-(N-methyl)-amino-benzoyl glutamic acid has been made from p-iodobenzoylglutamic acid and methyl amine in the presence of caustic soda solution at a pH of 8 to 9 and a copper catalyst [Cosulich and Smith, J. Am. Chem. Soc. 70, 1922 (1948)]. The process is characterized by the very expensive iodine derivatives used as starting products, and the reproduceability of the values is not guaranteed.
According to Fu, Reiner and Loo, J. Org. Chem. 30, 1277 (1965), p-(N-methyl)-aminobenzoyl glutamic acid can be produced from p-(N-methyl)-aminobenzoic acid, which is converted into its acid chloride. The acid chloride is reacted with diethyl-L-glutamate to obtain the corresponding amino benzoyl glutamic acid ester. The latter is hydrolyzed into the acid. The (N-methyl)-amino group of the p-(N-methyl)-aminobenzoic acid is protected by reaction with carbobenzyl oxychloride. Such means that a protective agent must be used which is too expensive for an industrial scale operation. [In addition, applicants have found that the process was not reproduceable with regard to its first step. Only benzyl oxycarbonyl-methyl aminobenzoic acid which was heavily contaminated with p-(N-methyl)-aminobenzoic acid, was obtained.]
D. V. Santi, J. Heterocycl. Chem. 4, 475 (1967), teaches producing the p-(N-methyl-N-tosyl)-aminobenzoic acid, starting from ethyl-p-aminobenzoate by first achieving therefrom ethyl-p-(N-tosyl)-aminobenzoate. The latter is chlorinated into p-(N-methyl-N-tosyl)-amino benzoyl chloride. Diethyl-p-(N-methyl-N-tosyl)-amino benzoyl glutamic acid ester by reacting the latter with diethyl-L-glutamic hydrochloride. After another reaction step, the diethyl-p-(N-methyl)-aminobenzoyl-L)-glutamate is arrived at. The method is very cumbersome with regard to the large number of synthesis steps and is therefore not particularly suitable for industrial use.